PBPK Model of Morphine Incorporating Developmental Changes in Hepatic OCT1 and UGT2B7 Proteins to Explain the Variability in Clearances in Neonates and Small Infants

Abstract

Morphine has large pharmacokinetic variability, which is further complicated by developmental changes in neonates and small infants. The impacts of organic cation transporter 1 (OCT1) genotype and changes in blood‐flow on morphine clearance (CL) were previously demonstrated in children, whereas changes in UDP‐glucuronosyltransferase 2B7 (UGT2B7) activity showed a small effect. This study, targeting neonates and small infants, was designed to assess the influence of developmental changes in OCT1 and UGT2B7 protein expression and modified blood‐flow on morphine CL using physiologically based pharmacokinetic (PBPK) modeling. The implementation of these three age‐dependent factors into the pediatric system platform resulted in reasonable prediction for an age‐dependent increase in morphine CL in these populations. Sensitivity of morphine CL to changes in cardiac output increased with age up to 3 years, whereas sensitivity to changes in UGT2B7 activity decreased. This study suggests that morphine exhibits age‐dependent extraction, likely due to the developmental increase in OCT1 and UGT2B7 protein expression/activity and hepatic blood‐flow.

Innovative approaches and recent advances in the study of ontogeny of drug metabolism and transport

“…This supposition is supported by a study concluding that hepatic OCT1 ontogeny partly explained the lower clearance of its substrate morphine in neonates and infants than in adults. 16 Regarding renal transporters, the renal clearance in general is driven by glomerular filtration, which also changes with age. The glomerular filtration rate (GFR) reaches 50% of adult values by 2 months and 90% of adult values by age 1 year.…”

Making Medicines Baby Size: The Challenges in Bridging the Formulation Gap in Neonatal Medicine

“…Comprehensive physiologically based pharmacokinetic modelling (PBPK) systems have been introduced that replicate the known parameters of the paediatric GI tract to better predict oral dosing [174,175,176,177,178,179,180,181,182]. However, the major limitation in both in vitro and in silico models is the lack of accurate knowledge about the neonatal and infant intestinal parameters [178,183,184].…”

Suggestions for Model‐Informed Precision Dosing to Optimize Neonatal Drug Therapy

“…A recent study showed that morphine exhibits age-dependent extraction as a result of developmental increases in OCT1 and UGT2B7 protein expression/activity and hepatic blood flow. 33 This temporal versus pharmacogenomics contribution to drug response in neonates is further demonstrated by cytochrome P450 (CYP)2C8*3, CYP2C9*2, and CYP2C9*3 polymorphisms that show lower ibuprofen clearance in adults. 34 It might be assumed that genetic polymorphisms that reduce drug clearance would increase ibuprofen effectiveness, but these polymorphisms have no effect in the ductus arteriosus response to ibuprofen in preterm infants.…”

“…Determining the age when genetic variations become the predominant factor for differences in drug response is crucial to evidence‐based dosing algorithms in neonates. A recent study showed that morphine exhibits age‐dependent extraction as a result of developmental increases in OCT1 and UGT2B7 protein expression/activity and hepatic blood flow . This temporal versus pharmacogenomics contribution to drug response in neonates is further demonstrated by cytochrome P450 (CYP)2C8*3, CYP2C9*2, and CYP2C9*3 polymorphisms that show lower ibuprofen clearance in adults .…”